IGF-1 Reduces Inflammatory Responses, Suppresses Oxidative Stress, and Decreases Atherosclerosis Progression in ApoE-Deficient Mice

Abstract

Objective-Whereas growth factors, via their ability to stimulate vascular smooth muscle cell (VSMC) proliferation and migration, have been thought to play a permissive role in atherosclerosis initiation and progression, the role of insulin-like growth factor-1 (IGF-1) is unknown. Here we report for the first time that IGF-1 infusion decreased atherosclerotic plaque progression in ApoE-deficient mice on a Western diet. Methods and Results-ApoE-null mice (8 weeks) were infused with vehicle or recombinant human IGF-1 and fed a high-fat diet for 12 weeks. Analysis of aortic sinuses revealed that IGF-1 infusion decreased atherosclerotic plaque progression and macrophage infiltration into lesions. Furthermore, IGF-1 decreased vascular expression of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-␣, reduced aortic superoxide formation and urinary 8-isoprostane levels, and increased aortic pAkt and eNOS expression and circulating endothelial progenitor cells, consistent with an antiinflammatory, antioxidant, and prorepair effect on the vasculature. Conclusions-Our data indicate that an increase in circulating IGF-1 reduces vascular inflammatory responses, systemic and vascular oxidant stress and decreases atherosclerotic plaque progression. These findings have major implications for the treatment of atherosclerosis. Key words: insulin-like growth factor Ⅲ atherosclerosis Ⅲ apolipoprotein E Ⅲ inflammatory response Ⅲ oxidative stress A therosclerosis is the principal underlying cause of most cardiovascular disease-related deaths, the leading cause of mortality in the USA. 1 Long considered to result from progressive vascular lipid accumulation, atherosclerosis is now recognized as a chronic inflammatory disease, 2-5 in which oxidative stress plays a key initiating role. Thus, multiple oxidative stimuli including oxidation of low-density lipoprotein (LDL) in the subendothelial space can result in endothelial cell adhesion molecule expression, monocyte and T cell recruitment, and macrophage lipid accumulation and foam cell formation. 6 Growth factors, cytokines, chemokines, and proteases modulate many steps in the atherosclerotic process including the migration and proliferation of smooth muscle cells. Furthermore, vascular and extravascular progenitor cells contribute to atherogenesis, and these include circulating endothelial progenitor cells (EPCs) that are likely part of a vascular repair system. 7 Insulin-like growth factor-1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that is the primary mediator of the effect of growth hormone (GH) on developmental growth. 8 IGF-1 is expressed in vascular cells 9 and in monocyte/macrophages, 10,11 but its role in atherogenesis is unknown. IGF-1 is a mitogen for endothelial cells 12 and vascular smooth muscle cells, 13 and can potentiate endothelial cell TNF-␣-induced c-Jun and NF-B activation. 14 Furthermore, IGF-1 has potent survival effects on vascular cells and prevents oxidized LDL-induced apoptosis of vascular smooth muscle cells. 15 We ha...

Endothelial cells and the IGF system

“…This is supported in part by a population study demonstrating that flow-mediated dilation, a measure of endothelial function, correlated with serum IGF1 levels in adult men but not women (Empen et al 2010). IGF1 infusion increased the number of circulating EPCs and reduced inflammation and oxidative stress in the Apoe-null mouse model of atherosclerosis (Sukhanov et al 2007). Additionally, IGF1 secreted by EPCs mediated myocardial repair after myocardial infarction in a porcine model (Hynes et al 2013).…”

Insulin-like Growth Factor-1 Increases Synthesis of Collagen Type I via Induction of the mRNA-binding Protein LARP6 Expression and Binding to the 5′ Stem-loop of COL1a1 and COL1a2 mRNA

“…We have shown previously that IGF-1 reduces atherosclerosis in ApoE-deficient mice (19,20). IGF-1 infusion and SMCspecific IGF-1 overexpression increases features of plaque stability including up-regulation of plaque collagen levels (19,21), however the mechanism mediating this effect has not been identified.…”

“…Therefore, collagen content in plaque is established as a major hallmark of plaque stability (15)(16)(17)(18). Our previous studies in vivo have shown that IGF-1 infusion in Apoe Ϫ/Ϫ mice significantly reduced oxidative stress and atherosclerosis, and increased plaque collagen (19,20). SMC-specific IGF-1 overexpression did not change atherosclerotic plaque burden, but did increase collagen content in atherosclerotic plaque together with other features of plaque stability (21).…”

IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis

“…Endothelial dysfunction and oxidative stress IGF-1 is known to exert multifaceted vasoprotective effects (Bailey-Downs et al 2012a, b;Csiszar et al 2008;Higashi et al 2010Higashi et al , 2012Sonntag et al 2013;Sukhanov et al 2007;Ungvari and Csiszar 2012;Ungvari et al 2010) but the role of developmental IGF-1 deficiency in regulating vascular aging has never been investigated. We found that endothelium-dependent aorta relaxation induced by acetylcholine was significantly impaired in aged control mice as compared to young control mice (Fig.…”